The Colon Cancer Family Registry (C-CFR) is a multicenter infrastructure, initiated by NIH in 1997, with a goal of accelerating multidisciplinary discoveries on colorectal cancer causes, prevention, and outcomes. Registry data and biospecimens are accessible to qualified researchers around the world. The Registry, which is now reaching maturity, is successfully meeting its mandate, as 150 collaborative projects are already underway or completed and applications for use of the Registry are increasing rapidly. Within the last ten years, the six C-CFR centers have consented and enrolled over 11,000 mostly population-based families that span the continuum from average risk through very high risk. Families are enrolled using standardized protocols for collection of family history, epidemiologic risk factors, blood collection, tumor tissue collection, and baseline phenotyping of tumors for DMA mismatch repair proficiency. Data is transmitted to a central informatics center and data from completed research studies are also transmitted, so data on each family is increasingly annotated over time. The Mayo C-CFR was selected as one of the original six C-CFR centers. Each center was selected for its potential complementary with the other centers to create a final entity that would optimally serve diverse types colorectal cancer research. The hallmark of the Mayo C-CFR is particular expertise in genetics and biospecimens, including both clinical and laboratory aspects. Mayo C-CFR has a notably well balanced and robust portfolio for recruitment and research contributions as well. In this renewal application, Aims were strategically prioritized and harmonized with all C-CFR sites to move colorectal cancer research forward as efficiently as possible. The Mayo Specific Aims include: 1) expand recruitment into families with known single-gene disorders;2) enroll 80 new very high risk families;3) follow-up 2,854 participants for vital status and new family history of cancers;4) ascertain and abstract medical records of cancer stage, treatments and outcomes;5) maintain high quality local Biospecimen repository and integrate with proposed Central Repository;6) support molecular characterization core by continuing tumor phenotyping, performing germline mutation analysis on MLH1, MSH2, and MSH6 for the entire C-CFR, and dispatching products to other CFR sites for characterization of somatic MLH1 methylation and BRAF analysis, germline PMS2 and MYH mutations;7) maintain local bioinformatics and data transmissions;8) maintain necessary administrative core to sustain the C-CFR.